HU187290B - Process for producing optically active phenyl-propane derivatives - Google Patents

Description

The present invention relates to novel optically active phenylpropane derivatives.

A 2,656,747; Fungicidal phenylpropane derivatives are already known from German Patent Publication Nos. 2,750,016 and 2,752,135. Particularly effective has been found the 1- [3- (p-tert-butylphenyl) -2-methyl] -cis-3,5-dimethylmorpholine of formula I having an asymmetric carbon atom (German Patent Publication No. 2,656,747). claim).

The (-) - enantiomer of this compound is more potent than the racemate. The racemate of Formula I can be prepared in a known manner, for example by reaction with (+) - camphorsulfonic acid in a diluent, by fractional crystallization of diastereomeric salts and by reacting a salt with a (-) - enantiomer with a strong base. document). However, this procedure for the separation of enantiomers is cumbersome, and the (+) enantiomer remaining in the mother liquor must be racemized to be used again for the separation of the enantiomers.

It has been found that the (-) - enantiomer can be easily synthesized from the appropriate optically active starting material without the formation of the undesired (+) enantiomer.

The present invention relates to a process of formula II

S-configuration phenylpropane derivatives. In this formula

R ^{1 is} hydrogen, (C 1 -C 4) -alkyl

C 1-4 alkoxy; R ^{2 is} hydrogen or C 1-4 alkoxy and R ^{3 is} hydroxymethyl.

To prepare compounds of formula II, a compound of formula III, wherein R ¹ and R ² are as defined above and R ^{4 is} CHO, is microbiologically hydrogenated.

In R ¹ the alkyl group is 1-4 carbon atoms, preferably tert-butyl group, C1-4 alkoxy radical, preferably tert-butoxy.

Preferably R ² is hydrogen.

Microbiological hydrogenation is carried out with the microorganism Saccharomyces cerevisiae (alcohol, beer, baker's yeast).

The microorganism may be cultured prior to use in fermentation; this is generally carried out in a known manner in an aqueous medium using the usual nutrients. It may sometimes be desirable to use the culture medium for fermentation, although the composition of the fermentation medium may be substantially simpler.

The fermentation can be carried out without additional additives only with the starting material and the microorganism, but it is preferable to add an assimilable carbon source to the aqueous medium, preferably in the amount of 10-100 g per liter, for example in the form of sugar, to keep the microorganism active. There is no need to add a nitrogen source; however, an assimilable nitrogen source may optionally be added in an amount of about 1-50 g / l. In addition, the fermentation medium may also contain inorganic salts and other growth promoters such as vitamins.

The fermentation is preferably carried out at a pH of from 2 to 10, in particular from 3 to 8; this can usually be achieved without any particular additives. Temperatures can be varied over a wide range, for example between 10 'C and 40' C, 20-35 'C being preferred. For optimal yield, it is preferred that the starting compound is present in a concentration of 0.1-5% in the fermentation medium. At the end of the reduction, the starting compound can always be added again until the microorganism is inactivated.

The fermentation time depends on the microorganism used and may be from 5 to 200 hours. Addition of the starting compound several times may increase the fermentation time appropriately.

The fermentation is preferably carried out under aerobic conditions, for example by maintaining the air in contact by stirring, shaking or by means of a ventilation device. Preferably, the microorganism is in a non-growing phase. Alternatively, dried or lyophilized cells may be used instead of freshly prepared cell weights. During microbiological hydrogenation, the aldehyde group (R ⁴ = CHO), if present, is reduced to the hydroxymethyl group.

The simple hydrogenation of the substituted cinnamaldehydes is surprising, since unsaturated methylphenylpropane derivatives are generally completely inert to microbiological effects or decarboxylated (Chem. Abstr. 91, 290; 35422).

II. compounds of the formula (II) can be converted to the corresponding tosylates or halogen derivatives which, with an amine such as a cis-dimethylmorpholine of the formula IV, wherein R ¹ and R ^{2 are} as defined above, become highly effective fungicides (2,656,747; German Federal Publications No. 2,752,096).

The following examples illustrate the invention.

Example 7 The following substances were charged into a (S) -3- (p-tert-butylphenyl) -2-methylpropanol (1) liter pure, non-sterilized fermenter:

deionized water 1.8 liters sucrose 90 g alcohol yeast 200 g

3- (p-tert-Butyl-phenyl) -2-methyl-2- 8 g in 30 ml of stepropen-1-ol

187 290 Silicone antifoam fermentation conditions: temperature mixer speed: ventilation rate:

'C 500 / min 1 vol. air / vol. medium / min fermentation time: 52.5 hours.

After 52.5 hours the fermentation was stopped. 1θ Cell mass is separated from the medium by centrifugation; both phases are extracted 3 to 3 times with methylene chloride. The combined extracts were dried over sodium sulfate and concentrated in vacuo.

The residue is distilled. Yield: 4.1 g (51%). [α] 20 = -7.54 °.

With proper optimization, the yield is easily increased. kozható.

The optical purity of the product was determined by nuclear magnetic resonance spectroscopy in the presence of a chiral shift reagent such as (Eu (hfbc) ₃ ).

The product consisted of only one enantiomer; Converted to (S) -1- [3- (tert-butylphenyl) -2-methylpropyl] cis-3,5-dimethylmorpholine, the S configuration was found.

Example 2

2-Methyl cinnamon alcohol derivatives In a round-bottomed flask heated to 'C', fill the following materials:

300 ml deionized water g sucrose 35 g dried yeast.

The contents of the flask were stirred at 300 rpm. 15 minutes after fermentation

1.5 g of the starting compound (substrate) was added and incubated for an additional 24 hours. After ₄ θ, the whole culture solution is extracted 3 times with methylene chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo.

The f. Compounds listed in Table II are obtained:

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Claims (1)

A process for the preparation of S-configuration phenylpropane derivatives of formula II in this formula R ^{1 is} hydrogen, C 1-4 alkyl or C 1-4 alkoxy; R ² is hydrogen or C1-4 alkoxy, and R ³ hydroxymethyl-group - wherein propariol phenyl derivative of formula III - in which R ¹ and R ² as defined above 5Q and R * CHO - Microbiologically hydrogenated with Saccharomyces cerevisiae at pH 2-10 at 10 to 40 ° C.